C9-ALS/FTD
IMED 7170
Overview
ALS-FTD
C9orf72
Healthy function
Hexanucleotide Repeat Expansion (HRE)
Pathogenic Mechanisms
Treatments
In the Clinic
Future Directions
ALS and FTD
Amyotrophic Lateral Sclerosis
Complex disease of motor neurons
Muscle and cognitive impairment
Familial and sporadic
Numerous molecular factors influence expression
ALS and FTD
Frontotemporal Dementia
Second most common form of pre-senile dementia
Frontal lobe degeneration and behavioral abnormalities
Familial and sporadic
Numerous molecular factors influence expression
ALS and FTD
ALS/FTD
Considerable clinical overlap
Shared Molecular Signatures / biomarkers
“Spectrum”
ALS and FTD
C9-related ALS/FTD
Why C9orf72?
- Healthy C9orf72
- HRE mutation
- Pathology
C9orf72
Healthy C9orf72
Gene Structure
Isoforms
Normal Gene Function
Distribution in the body
C9orf72
Hexanucleotide Repeat Expansion (HRE)
Structure
Variable Repeat Numbers
Incomplete Penetrance
Variable Expressivity
Somatic Instability
Repeat Contraction
C9orf72 Pathogenic Mechanisms
C9orf72 Pathogenic Mechanisms
Haploinsufficiency
Hypermethylation
Dysregulated C9orf72 function
Immune phenotypes
Additive Effects
C9orf72 Pathogenic Mechanisms
RNA Foci
G-quadruplex structure
Sequester RNA-binding proteins
Frontal Cortex (FTD) and Spinal Cord (ALS)
Nucleolar stress
C9orf72 Pathogenic Mechanisms
Dipeptide Repeat (DPR) Proteins
Repeat-associated non-ATG (RAN) translation
Different DPRs = Different mechanisms
Selective Neuronal Vulnerability
C9orf72 Pathogenic Mechanisms
Other Molecules
TDP-43
p62
TBK1
C9orf72-related ALS/FTD
Treatment
Antisense oligonucleotides (ASOs)
Small Molecule
Gene Therapy?
Timing and location
C9orf72-related ALS/FTD
Unknowns
Contribution of molecular mechanisms
Complex “interactome”
Familial vs. sporadic
